The present technology relates generally to the field of radiopharmaceuticals and their use in nuclear medicine for the treatment of various disease states. It is well known that tumors may express unique proteins associated with their malignant phenotype or may over-express normal constituent proteins as compared to the expression of these proteins in normal cells. The expression of distinct proteins on the surface of tumor cells offers the opportunity to diagnose, characterize ad treat disease conditions by using radiopharmaceutical compounds that selectively bind to specific tumor cell surface proteins. In particular, the present inventors have found that radiolabeled ligands that specifically bind to the CA-IX isoform of the enzyme carbonic anhydrase, often over-expressed on many cancer cells provides an attractive route for non-invasive and selective treatment of cancers.
While CA-IX is a membrane-anchored, its catalytic domain resides in the extracellular space. It has a limited tissue distribution and is found at low levels primarily in the gastrointestinal tract. The expression of CA-IX is under the control of HIF-1α, and this isozyme is highly expressed in rumors cells exposed to hypoxia both in vitro and in vivo. Increased CA-IX expression has been detected in carcinomas of the cervix, ovary, kidney, esophagus, lung, breast, and brain. It has been hypothesized that the low extracellular pH as a result of the activity of CA-IX leads to tumorigenic transformation, chromosomal rearrangements, extracellular matrix breakdown, migration and invasion, induction of growth factors, protease activation, and chemoresistance. Accordingly, a correlation can be made between the cellular levels of CA-IX and tumor progression. Radiopharmaceuticals directed to the CA-IX protein thus provide an novel avenue for the non-invasive treatment of cancer.
The selective targeting of cancer cells with radiopharmaceuticals is challenging. A variety of radionuclides are known to be useful for radioimaging and radiotherapy, including Re-186, Re-188, Te-99m, Ga-67, In-111, I-123, and I-131. The present invention provides bifunctional molecules that comprise a specific receptor honing bioactive molecule covalently tethered to Pt, 64Cu, 186Re, 188Re, or 99mTc as tumor-selective imaging agents.